Hyperlipidemia is a condition which is characterized by an abnormal increase in serum lipids, such as cholesterol, triglycerides and phospholipids. These lipids do not circulate freely in solution in plasma, but are bound to proteins and transported as macromolecular complexes called lipoproteins. There are five classifications of lipoproteins based on their degree of density: chylomicrons; very low density lipoproteins (VLDL); low density lipoproteins (LDL); intermediate density lipoproteins (IDL); and high density lipoproteins (HDL). Such classifications are commonly known to those of skill in the art and are described, for example, in the Merck Manual, 16th Ed. 1992 (see, for example, pp. 1039-1040) and “Structure and Metabolism of Plasma Lipoproteins” in Metabolic Basis of Inherited Disease, 6th Ed. 1989, pp. 1129-1138.
One form of hyperlipidemia is hypercholesterolemia, characterized by the existence of elevated LDL cholesterol levels. The initial treatment for hypercholesterolemia is often to modify the diet to one that is low in fat and cholesterol, coupled with appropriate physical exercise, followed by drug therapy when LDL-lowering goals are not met by diet and exercise alone. LDL is commonly known as the “bad” cholesterol, whereas HDL is the “good” cholesterol. Although it is desirable to lower elevated levels of LDL cholesterol, it is also desirable to increase levels of HDL cholesterol. Generally, it has been found that increased levels of HDL are associated with lower risk for coronary heart disease (CHD). See, for example, Gordon, et al., Am I. Med., 62:707-714 (1977); Stampfer, et al., N. England J. Med. 325:373-381 (1991); and Kannel, et al., Ann. Internal Med., 90:85-91 (1979).
Members of the nuclear hormone receptor superfamily function as ligand-dependent transcription factors that regulate genetic networks controlling important biological processes such as cell growth, development, and metabolism. In particular members of the Liver X Receptor (LXR) sub-group regulate transcription of genes involved in the coordinate regulation of cholesterol and lipid metabolism. The LXR subfamily of nuclear receptors is comprised of two iso-types, LXRα and LXRβ, which are encoded by independent genes. The two iso-types exhibit approximately 80% identity throughout their DNA binding and ligand binding domains. LXRα is highly expressed in liver, intestine, fat, and kidney, and expressed at lower, but detectable, levels in the adrenal gland, muscle, and cells of the hematopoetic system. In contrast, LXRβ is ubiquitously expressed in all tissues and cell types examined. Nevertheless, both iso-types are coexpressed in cell types that are involved in cholesterol metabolism and homeostasis such as hepatocytes (liver), intestinal enterocytes, and macrophages.
Numerous studies have shown that increased levels of HDL are associated with lower risks for cardiovascular disease. In contrast, elevated levels of non-HDL cholesterol lead to increased risks for cardiovascular disease. LXRα and LXRβ regulate several genes involved in HDL metabolism including those encoding the apolipoprotein ApoE, which is an essential component of the HDL particle, and the ATP binding cassette transporters ABCA1 and ABCG1. ABCA1 and ABCG1 function as efflux pumps that mediate the transfer of intracellular cholesterol out of cells to HDL particles, a process referred to as reverse cholesterol transport. Importantly humans with mutations in the ABCA1 gene suffer from Tangier disease and exhibit decreased levels of reverse cholesterol transport, decreased levels of HDL, and increased rates of coronary heart disease. Tangier disease patients also exhibit massive accumulation of cholesterol in their macrophages. Cholesterol laden macrophages are major components of atherosclerotic plaques and these cells are thought to play a key role in plaque formation and progression to cardiovascular disease.
The ability to control the efflux of intracellular cellular cholesterol is also important in the intestine. Studies have demonstrated that increasing ABCA1 levels limits the absorption of dietary cholesterol by stimulating the efflux of absorbed cholesterol out of enterocytes and into the intestinal lumen where it is excreted. An additional site of LXR activity is the liver where LXRs are involved in the expression of the CYP7a, the gene encoding the enzyme cholesterol 7α-hydroxylase. Cholesterol 7α-hydroxylase is the rate-limiting enzyme in the metabolic conversion of cholesterol to bile acids.
Some studies demonstrate that LXR agonists also produce significant increases in the level of serum triglycerides. High levels of serum triglycerides are known to increase the risk of cardiovascular disease and other metabolic diseases. Thus triglyceride elevation significantly decreases the therapeutic index of certain LXR agonists for the treatment of cardiovascular disease.
In view of the foregoing, there remains a need in the art for compounds and methods that can be used to regulate LXRs and, in turn, to control the balance of cholesterol metabolism and fatty acid biosynthesis. More particularly, there remains a need in the art for compounds and methods that can be used to increase HDL levels and, thus, to treat disorders associated with bile acid and cholesterol metabolism. The present invention fulfills these and other needs.